CN114432271A - 包含他达拉非的口腔崩解膜剂型 - Google Patents
包含他达拉非的口腔崩解膜剂型 Download PDFInfo
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- CN114432271A CN114432271A CN202011200326.0A CN202011200326A CN114432271A CN 114432271 A CN114432271 A CN 114432271A CN 202011200326 A CN202011200326 A CN 202011200326A CN 114432271 A CN114432271 A CN 114432271A
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- Prior art keywords
- acid
- orally disintegrating
- dosage form
- tadalafil
- film
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
本发明涉及一种作为有效成分包含他达拉非或者其药学上可接受的盐；以及作为成膜高分子的羟丙基纤维素以及普鲁兰多糖的口腔崩解膜剂型，由于给药方便性和吸收性优秀，可以非常有效地使用于服用他达拉非的患者。
Description
技术领域
本发明涉及一种包含他达拉非或者其药学上可接受的盐的口腔崩解膜剂型，具体地，涉及一种将包含他达拉非或者其药学上可接受的盐以及作为成膜高分子的羟丙基纤维素和普鲁兰多糖的口腔崩解膜剂型。
背景技术
他达拉非(tadalafil)是美国礼来制药公司以西力士(cialis)的商品名销售的治疗阳痿时使用的药物。1995年进行了国际申请并通过韩国授权专利第10-0357411号得到授权，但目前因专利权存续期限的结束而处于失效状态。化学名为(6R-反式)-6-(1，3-苯并二恶茂-5-基)-2，3，6，7，12，12a-六氢化吡嗪并-2-甲基-吡嗪并[1｀，2`∶1，6]吡啶并[3，4-b]吲哚-1，4-二酮，用作5型3’，5’-环鸟苷酸磷酸二酯酶(cGMP PDE5)的抑制剂，对平滑肌的松弛作用持续，血管扩张而具有血液供应量变通畅的效果。
阳痿的原因有高龄、吸烟、饮酒、糖尿、高血压、脑血管疾病、多发性硬化、慢性阻塞性肺疾病等，他达拉非不仅是在阳痿，还能有效作用于前列腺增生、阻塞性肺疾病等中。由于所述他达拉非的阳痿、前列腺增生等的用途特性，而不愿意告诉服用事实的情况较多。因此，相比现有的口服用药剂，无需水也能服用且携带方便的口腔崩解膜备受瞩目。
然而，他达拉非实质上具有不溶于水，不容易溶解在有机溶剂中的特性，因此在制备将其作为有效成分包含的口腔崩解膜时，需要能够改善药物的吸收性的方案。
为了制备口腔崩解膜而使用成膜剂，一般使用聚乙烯吡咯烷酮(polyvinylpyrrolidone，PVP)、羟丙基甲基纤维素(hydroxypropyl methylcellulose，HPMC)、聚乙二醇(polyethylene glycol，PEG)等。在韩国授权专利第10-1140110号以及韩国公开专利第10-2015-0048409号中公开了包含他达拉非的药学组合物的载体或者作为聚合物的羟丙基甲基纤维素或者聚乙二醇等。然而，使用该类高分子制备口腔崩解膜剂型时，具有难以达到优秀的崩解性以及早期高的药物浓度等效果的问题。
为此，本发明人致力于研究在包含他达拉非的口腔崩解膜剂型中能够同时改善崩解速度和吸收性的剂型，其结果开发出具有优秀的制剂学效果的口腔崩解膜型药剂学制剂，由此完成了本发明。
【现有技术文献】
【专利文献】
(专利文献1)韩国授权专利第10-1140110号
(专利文献2)韩国公开专利第10-2015-0048409号
发明内容
技术问题
本发明涉及一种相比一般的口服用剂型，无需水也能服用，提高服药的方便性的口腔崩解膜剂型，其目的在于，提供一种相比现有公知的口腔崩解剂型，崩解性以及吸收性等制剂学特性改善的口腔崩解膜剂型。
解决问题的手段
为了达成所述目的，本发明提供一种口腔崩解膜剂型，其中，包含他达拉非或者其药学上可接受的盐以及作为成膜高分子的羟丙基纤维素以及普鲁兰多糖。
在一实施形态中，可以为一种口腔崩解膜剂型，其中，所述羟丙基纤维素和普鲁兰多糖的重量比为1∶1至1∶10。
在一实施形态中，可以为一种口腔崩解膜剂型，其中，所述羟丙基纤维素和普鲁兰多糖的重量比为1∶3至1∶9。
在一实施形态中，可以为一种口腔崩解膜剂型，其中，所述剂型用于预防或者治疗阳痿、前列腺增生或者肺动脉高压。
发明效果
本发明涉及一种包含他达拉非的口腔崩解膜剂型，其无需水也能服用，提高服药的方便性，相比现有公知的口腔崩解膜剂型，具有改善的崩解速度以及迅速的早期吸收效果，可以有效地使用于服用他达拉非的患者。
附图说明
图1示出利用注射器的崩解实验方法。
图2是示出利用注射器的崩解实验结果的图表。
图3是示出将比较例2以及实施例2的剂型投入到比格犬之后，药物吸收结果的图表。
具体实施方式
以下，参考附图详细说明本文的实施形态以及实施例以供本发明所属技术领域中具有通常知识的人能够容易实施。然而，本文可以体现为多种形态，不限于在此说明的实施形态以及实施例。
在本文的整个说明书中，当涉及到某一部分“包含”某一构成要素时，没有特别相反记载的情况下，是指不排除其他构成要素而还可以包含其他构成要素。
本发明涉及一种将包含他达拉非或者其药学上可接受的盐以及作为成膜高分子的羟丙基纤维素以及普鲁兰多糖的口腔崩解膜剂型。
所述“他达拉非”是磷酸二酯酶(PDE)5抑制剂，不仅是他达拉非，他达拉非的溶剂化物或者水合物皆属于本发明的范围。
所述“药学上可接受的盐”是指对患者无毒性且无害，所述盐引起的副作用不降低本发明的化合物的有益功效的任意的酸加成盐或者碱加成盐。形成合适的盐的无机酸有盐酸、磷酸、硫酸、硝酸、酒石酸、氢溴酸、氢碘酸、亚硝酸或者亚磷酸等，形成合适的盐的有机酸有乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、苯甲酸、苯乙酸、肉桂酸、水杨酸、烟酸、对甲苯磺酸、樟脑磺酸、萘甲酸、乙酸、三氟乙酸、草酸、扁桃酸、丙酸、柠檬酸、乳酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡萄糖醛酸、天门冬氨酸、羧酸、香草酸、苯磺酸、p-甲苯磺酸或者甲基磺酸等，然而不限于此。
所述“口腔崩解膜(Oral Disintegrating Film，ODF)”也被称作条状(strip)口腔速溶膜(orally dissolving film)，是指可以在口腔(oral cavity)内溶解或者进行细微分散来服用的膜剂型。所述膜大致上是放在舌上进行融化，也可以是粘在上颚、舌下、口腔内部(buccal)等来给药。根据本发明的膜剂型具有无需水也能服用的优点。
本发明的剂型可以包含用于制备口腔崩解膜的成膜高分子，作为成膜高分子，最优选为羟丙基纤维素以及普鲁兰多糖。
本发明的发明人确认到在包含他达拉非的口腔崩解膜剂型中，作为所述成膜高分子同时包含羟丙基纤维素以及普鲁兰多糖时，具有优秀的崩解速度以及改善的吸收性、血液中浓度。
在本发明的剂型中，羟丙基纤维素和普鲁兰多糖的重量比可以为1∶1至1∶10，更加优选为1∶3至1∶9。
所述“普鲁兰多糖(pullulan)”是将由出芽短梗霉(Aureobasidium pullulans)所产生的多糖类进行分离·提纯而获得的物质，主要成分为中性多糖类。易溶于水，不溶于醇类和油类。相比其他胶类，属于粘度低的物质，然而在酸、碱、热等中稳定，除了成膜性之外，具有强的粘接性。普鲁兰多糖使产品具有柔软的触感，使凝胶组织变稳定。普鲁兰多糖相比明胶或者羟丙基甲基纤维素，具有如下优点：由于是非动物性起源，是没有任何化学改质的完全天然物质；通过调整发酵过程而具有高度一定的生产质量；形成具有高均质性和透明性的膜；通过非常低的氧透过性以及低的含水量而有利于保存产品；以及保存中具有高度的稳定性等。
根据本发明的膜可以进一步包含选自由表面活性剂、增塑剂、增味剂、崩解剂以及其混合物而成的组中的药学上可接受的添加剂。
另外，本发明的剂型涉及一种口腔崩解膜剂型，其特征在于，所述剂型用于预防或者治疗阳痿、前列腺增生或者肺动脉高压。
以下，通过实施例更加详细说明本发明，然而以下实施例仅是用于说明的目的，并不限定本文发明的范围。
【比较例1至3】
作为成膜高分子包含HPMC(羟丙基甲基纤维素)的他达拉非口腔崩解膜剂型
按照以下表1的组成，改变HPMC的含量，制备包含他达拉非的比较例1至3的口腔崩解膜剂型。
按照以下表1的成分以及含量，制备含有他达拉非的口腔崩解型膜制剂。表1的含量表示以7.5cm2的大小截取的单位制剂中的含量(mg)。向纯净水添加表1中记载的成分，并均匀混合。将获得的混合物在真空下利用桨叶搅拌约4小时去除气泡，将脱气的混合物以一定的厚度涂覆在PET膜(Enterpack公司)上之后，在70℃下干燥20分钟。获得的制剂的厚度约为0.1mm。将获得的制剂以7.5cm2的大小截取，从而制备口腔崩解型膜制剂。
【表1】
【实施例1至3】
作为成膜高分子包含普鲁兰多糖的他达拉非口腔崩解膜剂型
按照以下表2的组成，改变普鲁兰多糖的含量，制备包含他达拉非的实施例1至3的口腔崩解膜剂型。
按照以下表2的成分以及含量，制备含有他达拉非的口腔崩解型膜制剂。表2的含量表示以7.5cm2的大小截取的单位制剂中的含量(mg)。向纯净水添加表2中记载的成分，并均匀混合。将获得的混合物在真空下利用桨叶搅拌约4小时去除气泡，将脱气的混合物以一定的厚度涂覆在PET膜(Enterpack公司)上之后，在70℃下干燥20分钟。获得的制剂的厚度约为0.1mm。将获得的制剂以7.5cm2的大小截取，从而制备口腔崩解型膜制剂。
【表2】
【实验例1】
通过人工唾液的崩解实验
在塑料盘放置无纺布，在其上放置所述比较例1至3以及实施例1至3的试验膜1枚之后，利用注射器向膜中央以每分钟1ml滴入人工唾液。测定出现孔为止所消耗的时间，由此测定崩解能力，将该结果示于图2中。
如图2所示，确认到比较例1至3的剂型均消耗超过100秒的时间，然而实施例1至3的剂型消耗低于100秒的时间。因此，可以了解到实施例的剂型相比比较例的剂型，具有2至6倍以上的优秀的崩解效果。
【实验例2】
在比格犬中的药物吸收实验
将8只比格犬按照以下表3进行分组，实施吸收实验。
【表3】
将上述比较例2以及实施例2的剂型(口腔崩解膜)1枚放在比格犬的舌上稍微等待之后，确认膜是否消失，对每只比格犬随着时间采血之后，利用LC-MS/MS分析血液中他达拉非药物浓度，将该结果示于以下表4以及图3中。
【表4】
如所述表4以及图3中所示，确认到实施例的剂型相比比较例的剂型，显示2倍左右的优秀的吸收率以及更加迅速的药物吸收效果。
Claims (4)
1.一种口腔崩解膜剂型，其特征在于，包含：
他达拉非或者其药学上可接受的盐；以及
作为成膜高分子的羟丙基纤维素以及普鲁兰多糖。
2.根据权利要求1所述的口腔崩解膜剂型，其特征在于，羟丙基纤维素和普鲁兰多糖的重量比为1∶1至1∶10。
3.根据权利要求1所述的口腔崩解膜剂型，其特征在于，羟丙基纤维素和普鲁兰多糖的重量比为1∶3至1∶9。
4.根据权利要求1所述的口腔崩解膜剂型，其特征在于，所述剂型用于预防或者治疗阳痿、前列腺增生或者肺动脉高压。
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| KR20110041412A (ko) * | 2009-10-15 | 2011-04-21 | (주)씨엘팜 | Ｐｄｅ5 억제제를 함유하는 구강 용해성 필름 |
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